1. Field of the Invention
The present invention relates to ionic liquid type crown derivatives for isolating metal ions, a method for preparing the same and a method for selectively isolating metal ions using the same.
2. Description of Related Art
In general, nuclear medicine technologies for using nuclear power in medicine definitely require the use of a radiopharmaceutical. The radiopharmaceutical is prepared by selecting an appropriate material from among various kinds of radioactive isotopes generated when operating a nuclear reactor and processing it for use in the diagnosis or therapy of diseases to be administered to the human body. Such a radiopharmaceutical can readily and obviously detect metastasis of cancer that is difficult or impossible to diagnose using other techniques.
These days, extremely small quantities of radioactive isotopes have been applied to the nuclear medicine field. Some radioactive isotopes such as 89Sr, 186Re, 153Sm, 90Y and 166Ho have been used in typical methods of medical therapy. These therapeutic methods have been studied to prepare the radiopharmaceuticals that irradiate noxious cells at high levels and most rapidly and do not damage healthy cells.
The radiopharmaceuticals have been applied in the field of radiographic imaging techniques. That is, according to the radiographic imaging technique, after injecting small quantity of radiopharmaceutical such as technetium-99m in the body, the distribution labeled by such radiopharmaceutical is detected to find pathologic diseases or to assess the symptom degrees. The radiopharmaceutical used as a labeling substance is named as a contrast agent. The contrast agent comprising a radionuclide that emits radiation and a chelating agent coordinated with the radionuclide should satisfy the required conditions that it maximizes the detection efficiency of the radionuclide and minimizes the amount of radiation absorbed in a patient. Accordingly, technetium-99m and rhenium-188 have been generally used as radionuclides that emit γ-rays and have a physical half-life shorter than the imaging time (A. Egli, et al. The Journal of Nuclear medicine, 1999, 40, 1913; Wan-yu Lin, et al. European The Journal of Nuclear medicine, 1997, 24, 590; European The Journal of Nuclear medicine, 1993, 20, 66; V. J. Lewington. Physics in medicine and biology, 1996, 41, 2027; Kazuyuki Hashimoto, et al. Applied radiation and isotopes, 1996, 47, 195).
The radiopharmaceuticals are applicable to the diagnosis and therapy of cancers since the radiopharmaceuticals readily and obviously detect metastasis of cancers that is difficult or impossible to diagnose via other techniques. Skeletal metastasis occurring commonly in several cancers such as breast cancer, prostate cancer, lung cancer and kidney cancer is a major cause of death in patients who suffer from those cancers. So far, bone imaging techniques using technetium-99m have been known as a most selective and rapid way to find the skeletal metastases of cancer cells.
The radiations that the radioactive isotopes emit can be roughly classified into γ-ray, β-ray and α-ray. Each of the radiations has a different permeability according to its kind. The permeability that permeates a material relates to wavelengths. The wavelengths of the radiations become shorter in sequential order of α-ray, β-ray and γ-ray. Thus, γ-ray has the highest permeability. In general, radionuclides that emit γ-rays of high permeability have been used for diagnosis and therapy of cancers.
Meanwhile, methods of using radionuclides that emit β-rays will attract scientific attention in the future. So far, only 32P-phosphate and strontium dichloride (89SrCl2) therapies have been approved to applied to patients having tolerances to other anodynes among patients suffering from severe bone pains caused by such breast cancer, prostate cancer, lung cancer, kidney cancer, etc., accompanied with the skeletal metastases. In case of the cancers accompanied with the skeletal metastases, a small quantity of radiation should be distributed to the radiosensitive bone marrow and the minimum quantity of radiation be applied to cellular tissue adjacent to the marrow, whereas, a high dosage should be irradiated to bone surfaces where the skeletal metastasis occurs. Accordingly, e.g., the 89Sr that does not emit γ-rays permeating to the insides of cells but emits pure β-rays has been used.
The 89Sr has a half-life of 50.6 days and emits β-energy of 0.583 MeV from at an average distance of about 1.5 mm from the bone. Sr2+ has the same pathway in the body as calcium and is attached to the mineral structure of the bone and, preferentially, to highly degenerated region such as metastasis damage region. A small amount of carrier-free 89Sr not attached among the 89Sr administered via 110 to 180 MBq of 89SrCl2 in vivo injection is discharged from the body within 14 days, the biological half-life.
However, since 89Sr does not emit γ-rays, it is difficult to visualize directly the region affected with 89Sr. Especially, 89Sr has been used for imaging the metastasis region in vivo using a collimator and an appropriate gamma camera, although such method is inefficient that bremsstrahlung radiation is emitted from β-rays and it has a wide energy spectrum.
As described in detail above, 89Sr occupy an important position as a radioactive isotope for the bond imaging and, for this purpose, it is necessary to provide methods for isolating and extracting 89Sr (C. Cipriani, et al. European The Journal of Nuclear medicine, 1997, 24, 1356; I. Csete, et al. Applied Radiation and Isotopes, 2002, 56, 467).
In addition to 89Sr, 90Y that emits beta particles has attracted attention. 90Y is a radioactive isotope having EβMax of 2.3 MeV and T1/2 of 64.1 h that does not emit γ-rays and is useful for therapy. Especially, 90Y has the properties of a half-life and a radioactive decay suitable for labeling a monoclonal antibody (Mab's) to be used for the therapeutic purpose of cancers. The 90Y is generated from 90Sr, a parent radionuclide, via the following radioactive decay process:

As shown in the decay process, the carrier-free 90Sr can be obtained continuously from the parent radionuclide 90Y theoretically. However, to prepare pure 90Y from a generator system, a high selectivity and a rapid isolation method are required. Especially, they are much required to apply the same to the nuclear medicine.
Meanwhile, in view of environmental samples, analyses of 90Sr and 90Y radioactive isotopes, the β-ray emitters, are very complicated as a matter of fact. Accordingly, it is necessary to chemically isolate the radioactive isotopes including 89Sr prior to their application in the nuclear medicine field (J. Donald, et al. Analytical Chemistry, 1993, 65, 1350; S. Malja, et al. Journal of Radioanalytical and Nuclear Chemistry, 2000, 245, 403).
Meanwhile, macrocyclic polyethers have attracted attention recently as a method for isolating chemical species. For example, the following compounds are included in the macrocyclic polyethers and referred to as crown ethers because they have crown shapes.

The first numerals of the compound names denote the number of atoms organizing a cycle, which expresses the size of the cycle. The second numerals of the compound names represent the number of oxygen out of the atoms organizing the cycle. The oxygen atoms are located generally between two carbon atoms.
The crown ethers have a characteristic that forms complexes with cations such as Na+, K+, etc. The cation enters selectively into the inside of the macrocyclic compound according to the sizes of cycle and cation. For example, as depicted in the following scheme, [18]crown-6 has a cavity diameter that is too broad for Na+ of small size to be situated therein and too narrow for Cs+ of large size to be settled therein. Accordingly, K+ forms a snug fit. Meanwhile, [15]crown-5 is bound with Na+ and [12]crown-4 is coupled with Cs+.

Since the crown ether has a strong capability of forming a complex, with some quantity of crown ether, it is possible to dissolve even an ionic compound in an organic solvent. For example, potassium permanganate (KmnO4) is not melted in benzene but well dissolved in water. However, if some quantity of dicyclohexyl [18]crown-6 is melted in benzene, the potassium permanganate dissolved in water can be extracted into benzene. The resultant “purple benzene” having permanganate ions, not eluted, is a strong oxidizer.
Recently, chiral crown ethers have been synthesized. These compounds coordinate with enantiomorphs of compounds satisfied with their chirality, but do not bond with the others. The chiral crown ethers are efficiently used for isolating racemic mixtures. In general, since enzymes have a capability for discriminating enantiomorphs, the chiral crown ethers have been studied as the form of enzymes.
Selective bondings of metal ions via the macrocyclic compounds occupy an important position in the natural world. For example, an antibiotic such as nonactin includes a macrocycle having oxygen atoms taking up fixed spaces. Nonactin, having four THF cycles bonded with four ester bonds, selectively bonds K+ and Na+ in water-soluble medium and carries K+, not Na+, via cell membrane (C. J. Pedersen, Journal of the American Chemical Society, 1967, 89, 7017).
Ionic liquid type crown ether (IL-CE) is composed of crown ether molecules, having the above-described features, introducing a functional group of ionic salts that execute a function of ionic liquid.
The ionic liquid denotes ionic salts that exist liquidly at 100° C. or less, like salt, differently from ionic salt compounds composed of metallic cations and nonmetallic anions melted at a high temperature of 800° C. or more. Especially, ionic liquid existing liquidly at room temperature is referred to as room temperature ionic liquid (RTIL). The ionic liquid is composed of organic cations and anions as shown in the following figure.

Since general organic solvent has a vapor pressure, the temperature for use of the organic solvent is limited and it is readily burnt out when it comes up close to fire. Besides, when introducing a specific structure to increase polarity, viscosity of the solution is increased due to interactions of molecules. However, the ionic liquid is a liquid having features of salt. Especially, the room temperature ionic liquid has a variety of features such as non-volatility, non-toxicity, non-combustibility, excellent heat-stability, ionic conductivity and the like. Furthermore, the room temperature ionic liquid having a high polarity dissolves inorganic and organometallic compounds well and exists liquidly at a wide range of temperature. Moreover, the room temperature ionic liquid has attractive features that it is a green reagent that is harmless to human being and is recyclable.
The ionic liquid having the above described various features can be applied in the intensive chemical fields as an enzyme for increasing the reaction rate, a green solvent that is recyclable after reaction, a medium for isolating and extracting a reaction product, applications in nano-chemistry, an electrolyte in electrical chemistry, a supercritical fluid and the like. Besides, according to the physicochemical properties of the ionic liquid, it is possible to readily synthesize an ionic liquid that coincides with a desired use since the ionic liquid can regulate the structures of cation and anions constituting the ionic liquid. Accordingly, the ionic liquid has been referred to as a designer solvent (Ionic liquids: Industrial application for green chemistry, American Chemical Society, 2002).
The above described crown ethers have limitations that it is difficult to synthesize such ethers by cycle sizes, they are of high cost and they are not recyclable. However, the ionic liquid type crown ethers have advantages that they can be readily synthesized using cheap starting materials via simplified organic synthetic methods and, especially, can be synthesized by cycle sizes. Besides, the ionic liquid type crown ethers can be used for selectively isolating and extracting a variety of metal ions since they have the same capability for selectively chelating metal ions according to cycle sizes as the crown ethers. Furthermore, the ionic liquid type crown ethers showing the features of the ionic liquid at the same time have a complete ionicity that is not provided by only the conversion of the functional group of crown ethers and have physical and chemical features different from the existing crown ethers, thus being used as a recyclable green reagent.